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  • ISSN: 1756-2856 http://tan.sagepub.com

    Therapeutic Advances in

    Volume 1 Number 1 October 2008

    Medical Oncology

    Therapeutic Advances in

    Medical Oncology

    ISSN: 1756-2856 http://tam.sagepub.com

    Reprinted from Volume 10, 2018

    Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors

    VVeerraa HHiirrsshh

    http://tam.sagepub.com/

  • https://doi.org/10.1177/1758834017753338 https://doi.org/10.1177/1758834017753338

    Therapeutic Advances in Medical Oncology

    journals.sagepub.com/home/tam 1

    Ther Adv Med Oncol

    2018, Vol. 10: 1 –12

    DOI: 10.1177/ 1758834017753338

    © The Author(s), 2018. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

    Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

    Introduction Patients with non-small-cell lung cancer (NSCLC) represent a heterogeneous population, making disease management challenging; how- ever, increased understanding of the molecular pathogenesis of the disease has paved the way for new treatments using molecularly targeted anti- cancer agents.1 Currently, the most established target is the epidermal growth factor receptor (EGFR),1 a member of the ErbB kinase family of structurally related receptor tyrosine kinases. In humans, the ErbB family consists of EGFR (HER1, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4).2

    ErbB proteins play a number of key roles in the regulation of cellular proliferation, and their dys- regulation has been identified in a variety of can- cers.2 For example, somatic mutations of EGFR have been reported in approximately 50% of Asian patients and 10–15% of Caucasian patients with lung adenocarcinoma,3 with the most com- mon mutations in these populations being exon 19 deletions (Del19) and an L858R point muta- tion (L858R).4 Importantly, in a phenomenon known as ‘oncogene addiction’, tumors bearing EGFR mutations have been observed to become dependent on EGFR signaling pathways for their survival and growth.5,6

    Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors Vera Hirsh

    Abstract: Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first- (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles. Therefore, there is a strong imperative to optimize the sequence of TKIs in order to maximize their clinical benefit. Osimertinib has demonstrated striking efficacy as a second- line treatment option in patients with T790M-positive tumors, and also confers efficacy and tolerability advantages over first-generation TKIs in the first-line setting. However, while accrual of T790M is the most predominant mechanism of resistance to erlotinib, gefitinib and afatinib, resistance mechanisms to osimertinib have not been clearly elucidated, meaning that possible therapy options after osimertinib failure are not clear. At present, few data comparing sequential regimens in patients with EGFR mutation-positive NSCLC are available and prospective clinical trials are required. This article reviews the similarities and differences between EGFR TKIs, and discusses key considerations when assessing optimal sequential therapy with these agents for the treatment of EGFR mutation-positive NSCLC.

    Keywords: acquired resistance, EGFR mutations, EGFR TKI, NSCLC, T790M

    Received: 25 August 2017; revised manuscript accepted: 19 December 2017.

    Correspondence to: Vera Hirsh McGill Department of Oncology, Royal Victoria Hospital, Glen Site, 1001 Décarie Blvd, Montreal, QC H4A 3J1, Canada vera.hirsh@muhc.mcgill. ca

    753338 TAM0010.1177/1758834017753338Therapeutic Advances in Medical OncologyV Hirsh review-article2018

    Review

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  • Therapeutic Advances in Medical Oncology 10

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    Four EGFR tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, afatinib and osimertinib) are currently available for the management of NSCLC, while others are in development.7 Of the available TKIs, erlotinib, gefitinib and afatinib are the first-line standard of care in patients with EGFR mutation-positive NSCLC, as supported by robust phase III data.8–15 Erlotinib and gefi- tinib were the earliest small-molecule inhibitors to be approved for NSCLC and are generally referred to as first-generation EGFR TKIs. These agents block receptor tyrosine kinase activity by reversibly binding at or near the adenosine triphosphate binding site on the intracellular kinase domain.16 Afatinib is a second-generation ErbB family blocker, which irreversibly blocks signaling from all relevant homo- and heterodi- mers of the ErbB family of receptors.17 Other second-generation EGFR TKIs, such as dacomi- tinib, are currently in development.7

    Despite the proven activity of EGFR TKIs in a first-line treatment setting, patients inevitably develop acquired resistance. The most common resistance mechanism, identified in at least 50– 70% of tumors, proceeds through accumulation of the so-called ‘gatekeeper’ T790M mutation in exon 20 of EGFR.18–21 Osimertinib is a third-gen- eration EGFR TKI with low selectivity for wild- type EGFR and high potency toward T790M. In the phase I/II AURA trial and subsequent phase III AURA 3 trial, osimertinib demonstrated strik- ing efficacy, with response rates of approximately 60–70%, in patients with acquired resistance to erlotinib, gefitinib or afatinib and T790M- positive tumors, and is approved in this set- ting.21–23 Of note, only 7% of patients treated with osimertinib in AURA 3 were previously treated with afatinib.23 Osimertinib also showed promis- ing results in a first-line setting; in an expansion cohort of AURA, an objective response rate (ORR) of 77% was achieved, with progression- free survival (PFS) of 19.3+ months, as well as manageable tolerability.24 On the basis of these findings, first-line osimertinib was recently assessed against gefitinib or erlotinib (but not afatinib) in the phase III FLAURA trial [ClinicalTrials.gov identifier: NCT02296125].25 FLAURA achieved its primary endpoint of PFS; osimertinib was associated with a striking improvement of ~9 months in median PFS versus first-generation EGFR TKIs,25 thus positioning it as a first-line treatment option. However, mecha- nisms of resistance to osimertinib and treatment options following acquired resistance remain

    uncertain. Other third-generation EGFR TKIs currently in development include olmutinib (approved in South Korea), ASP8273, nazarti- nib, PF-06747775, avitinib and HS-10296.7

    With the currently approved EGFR TKIs, and the potential approval of additional agents in the future, it is important to understand the similari- ties and differences between these agents in order to determine the most appropriate intervention for each patient. It is also essential that mecha- nisms of resistance are understood so that the sequence of therapy can be tailored to the molec- ular evolution of the tumor. This article reviews the available clinical data in this regard, and dis- cusses key considerations when assessing optimal sequential therapy with EGFR TKIs for the treat- ment of EGFR mutation-positive NSCLC.

    Clinical trial data supporting the first-line use of EGFR TKIs in EGFR mutation-positive NSCLC

    Phase III clinical trials versus chemotherapy The use of first-line EGFR TKIs versus chemother- apy for patients with advanced EGFR mutation- positive NSCLC is supported by robust efficacy and tolerability data from numerous phase III tri- als, including the gefitinib trials, First-SIGNAL (subgroup analysis), IPASS (subgroup analysis), WJTOG3405, and NEJ0028–10,26–29; the erlotinib trials, OPTIMAL, EURTAC, and ENSURE11,14,15; and the afatinib trials, LUX-Lung 3 and LUX- Lung 6.12,13 Together, these trials unequivocally demonstrated that EGFR TKIs improve PFS ver- sus platinum-based chemotherapy, with a median PFS of 9.2–11.1 months reported with EGFR TKIs across the trials compared with 4.6–6.9 months with platinum doublets.

    As well as demonstrating efficacy benefits, EGFR TKIs were generally tolerable. Although they were associated with a class-related safety profile with characteristic adverse events (AEs), including g